Critical research gaps remain in understanding 1) the link between HIV infection and disease; 2) host determinants for viral control; and 3) what immune responses are needed to protect individuals from HIV infection and/or disease. Non-human primate (NHP) models have been invaluable in developing paradigms for HIV-1 infection in humans and vaccine research that can inform human trials. However, NHP models are still needed that can reliably and robustly address viral/host determinants and mechanisms that underlie host control and protection from infection. During the 3 year award of AI074362, our laboratory has validated a powerful and novel NHP model to study host control of SIVmac in pigtail macaques (PTMs), a NHP species now recognized as being highly susceptible to SIV-induced disease. We have shown that when SIVmac239, which reproducibly causes AIDS in PTMs, contains a mutation that ablates a GYxxO trafficking signal in the Env TM cytoplasmic tail, the resulting virus, termed ?GY, replicates to a high acute RNA peak comparable to that of SIVmac239, but with the onset of host immune responses is suppressed to undetectable levels. These animals exhibit only a mild and transient reduction in CD4/CCR5 T-cells in gut lymphoid tissue and maintain normal numbers of peripheral CD4 T-cells for months to years. Importantly, ?GY-infected PTMs have been protected from homologous SIVmac239 challenges and able to control an i.v. infection of a pathogenic heterologous SIV (E660) suggesting that immune responses that can control ?GY are also effective against genetically diverse, pathogenic SIVs. In vitro ?GY virions contain less Env and become highly neutralization sensitive indicating that basic mechanisms at the cellular level, which underlie this novel in vivo phenotype, can be explored. Four aims are proposed to further extend the development of this model: Aim #1 will evaluate host determinants that are required for this elite control in ?GY-infected PTMs; Aim #2 will define host immune responses in ?GY-infected controllers that are relevant to protection and/or control of challenges with SIVmac239 and pathogenic, heterologous SIVs; Aim #3 will develop the unique ability of the ?GY model to explore underlying mechanisms by performing a comprehensive assessment of virologic, structural, genetic, and biochemical alterations in Env that are induced by the ?GY mutation; Aim #4 will extend the ?GY model of host control and protection to a pathogenic SHIV, where immune correlates of protection and control can be assessed in the context of an HIV-1 Env. In contrast to other NHP/SIV models, this PTM/?GY model provides a unique opportunity to link events at the viral/cellular interface to critical determinants of pathogenesis and to identify immune correlates that are relevant to control and protection.